Determination of the Structural and Pharmacokinetic Basis for Dihydropyridine Calcium Channel Blocker Activity: An In-Silico Investigation Targeting the L-Type Calcium Channel (CaV1.2)

Hypertension is a leading global health burden, with dihydropyridine calcium channel blockers (DHP CCBs) serving as a primary therapeutic class. However, the molecular and pharmacokinetic determinants underlying their variable clinical efficacy remain incom-pletely understood. This in silico study investigated the structural and ADME basis for the differential activity of five DHP drugs (amlodipine, nifedipine, isradipine, nicardipine, nisoldipine) targeting the L-type calcium channel CaV1.2. Molecular docking (Glide-XP), MM-GBSA binding free energy calculations using the human CaV1.2 structure (PDB: 8WE8), and ADME predictions (QikProp, CYP3A4 site of metabolism) were integrated. Results identified a conserved hydrogen bond with residue SER1132 (bond length range: 1.931–2.094 Å) as a key binding anchor. The Coulombic interaction energy (range: -74174.2 to -74202.3 kcal/mol) showed a strong inverse correlation with experimental IC₅₀ (0.013–0.194 µM), establishing it as a primary affinity determinant. Pharmacokinetically, predicted human serum albumin binding (QPlogKhsa: 0.237–0.770) directly correlated with IC₅₀, and metabolic vulnerability to CYP3A4 varied notably among the drugs. These findings demonstrate that the differential potency of DHP CCBs arises from a combination of target engagement strength, governed by electrostatic interactions and a conserved SER1132 anchor, and key ADME properties, providing a computational framework for ra-tional antihypertensive drug design.